title: Molecular evidence for a role for K(+)-Cl(-) cotransporters in the kidney.
abstract: K(+)-Cl(-) cotransporter (KCC) isoforms 3 (KCC3) and 4 (KCC4) are expressed at the basolateral membrane of proximal convoluted tubule cells, and KCC4 is present in the basolateral membrane of the thick ascending loop of Henle's limb and α-intercalated cells of the collecting duct. Little is known, however, about the physiological roles of these transporters in the kidney. We evaluated KCC3 and KCC4 mRNA and protein expression levels and intrarenal distribution in male Wistar rats or C57 mice under five experimental conditions: hyperglycemia after a single dose of streptozotocin, a low-salt diet, metabolic acidosis induced by ammonium chloride in drinking water, and low- or high-K(+) diets. Both KCC3 mRNA and protein expression were increased during hyperglycemia in the renal cortex and at the basolateral membrane of proximal tubule cells but not with a low-salt diet or acidosis. In contrast, KCC4 protein expression was increased by a low-sodium diet in the whole kidney and by metabolic acidosis in the renal outer medulla, specifically at the basolateral membrane of α-intercalated cells. The increased protein expression of KCC4 by a low-salt diet was also observed in WNK4 knockout mice, suggesting that upregulation of KCC4 in these circumstances is not WNK4 dependent. No change in KCC3 or KCC4 protein expression was observed under low- or high-K(+) diets. Our data are consistent with a role for KCC3 in the proximal tubule glucose reabsorption mechanism and for KCC4 in salt reabsorption of the thick ascending loop of Henle's loop and acid secretion of the collecting duct.
authors.affiliation: Molecular Physiology Unit, Vasco de Quiroga no. 15, Tlalpan 14000, Mexico City, Mexico. gamba@biomedicas.unam.mx.
authors.forename: Zesergio
authors.initials: Z
authors.lastname: Melo
authors.forename: Silvia
authors.initials: S
authors.lastname: Cruz-Rangel
authors.forename: Rocio
authors.initials: R
authors.lastname: Bautista
authors.forename: Norma
authors.initials: N
authors.lastname: Vázquez
authors.forename: María
authors.initials: M
authors.lastname: Castañeda-Bueno
authors.forename: David B
authors.initials: DB
authors.lastname: Mount
authors.forename: Herminia
authors.initials: H
authors.lastname: Pasantes-Morales
authors.forename: Adriana
authors.initials: A
authors.lastname: Mercado
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
mesh_terms: D000138:Acidosis / Q000139:chemically induced / Q000378:metabolism; D000643:Ammonium Chloride; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D004039:Diet, Sodium-Restricted; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017419:Potassium, Dietary / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D013311:Streptozocin; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D000643:Ammonium Chloride; D001786:Blood Glucose; D017419:Potassium, Dietary; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D013311:Streptozocin; D027981:Symporters; C492280:Slc12a6 protein, mouse; D000096922:K Cl- Cotransporters; C492281:Slc12a6 protein, rat; C492282:Slc12a7 protein, mouse; C492283:Slc12a7 protein, rat; C499024:Prkwnk4 protein, mouse
keywords: K+-Cl- cotransporter; acidosis; diabetes; low-salt diet